title: p73 deficiency results in impaired self renewal and premature neuronal differentiation of mouse neural progenitors independently of p53.
abstract: The question of how neural progenitor cells maintain its self-renewal throughout life is a fundamental problem in cell biology with implications in cancer, aging and neurodegenerative diseases. In this work, we have analyzed the p73 function in embryonic neural progenitor cell biology using the neurosphere (NS)-assay and showed that p73-loss has a significant role in the maintenance of neurosphere-forming cells in the embryonic brain. A comparative study of NS from Trp73-/-, p53KO, p53KO;Trp73-/- and their wild-type counterparts demonstrated that p73 deficiency results in two independent, but related, phenotypes: a smaller NS size (related to the proliferation and survival of the neural-progenitors) and a decreased capacity to form NS (self-renewal). The former seems to be the result of p53 compensatory activity, whereas the latter is p53 independent. We also demonstrate that p73 deficiency increases the population of neuronal progenitors ready to differentiate into neurons at the expense of depleting the pool of undifferentiated neurosphere-forming cells. Analysis of the neurogenic niches demonstrated that p73-loss depletes the number of neural-progenitor cells, rendering deficient niches in the adult mice. Altogether, our study identifies TP73 as a positive regulator of self-renewal with a role in the maintenance of the neurogenic capacity. Thus, proposing p73 as an important player in the development of neurodegenerative diseases and a potential therapeutic target.
authors.affiliation: Instituto de Biomedicina, Department of Molecular Biology, University of Leon Campus de Vegazana, Spain.
authors.forename: L
authors.initials: L
authors.lastname: Gonzalez-Cano
authors.forename: M
authors.initials: M
authors.lastname: Herreros-Villanueva
authors.forename: R
authors.initials: R
authors.lastname: Fernandez-Alonso
authors.forename: A
authors.initials: A
authors.lastname: Ayuso-Sacido
authors.forename: G
authors.initials: G
authors.lastname: Meyer
authors.forename: J M
authors.initials: JM
authors.lastname: Garcia-Verdugo
authors.forename: A
authors.initials: A
authors.lastname: Silva
authors.forename: M M
authors.initials: MM
authors.lastname: Marques
authors.forename: M C
authors.initials: MC
authors.lastname: Marin
mesh_terms: D000818:Animals; D002454:Cell Differentiation / Q000235:genetics*; D049109:Cell Proliferation; D004268:DNA-Binding Proteins / Q000235:genetics*; D005838:Genotype; D051379:Mice; D058953:Neural Stem Cells / Q000166:cytology*; D019636:Neurodegenerative Diseases / Q000235:genetics; D009474:Neurons / Q000166:cytology* / Q000378:metabolism; D009687:Nuclear Proteins / Q000235:genetics*; D000072160:Tumor Protein p73; D016159:Tumor Suppressor Protein p53 / Q000502:physiology*; D025521:Tumor Suppressor Proteins / Q000235:genetics*
chemical_list: D004268:DNA-Binding Proteins; D009687:Nuclear Proteins; C000606368:Trp73 protein, mouse; D000072160:Tumor Protein p73; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins